最新usp1092溶出度试验的开发和验证(中英文对照版)资料

1、(1092)溶出度试验的开发和验证【中英文对照版】INTRODUCTION.、八、-刖言Purpose目的The Dissoluti on Procedure: Developme ntand Validati on <1092> provides a comprehensive approachcoveringitemsto con siderfor develop ing and validati ng dissoluti on procedures and the accompa nyingan alytical procedures. It addresses the us

2、e of automati on throughout the testa nd providesguidaneeand criteria for validation.It also addressesthetreatme nt of the data gen erated and the in terpretati on of acceptanee criteriafor immediate- and modified-release solid oral dosage forms.溶出实验：开发和验证（1092 ）指导原则提供了在溶出度方法开发和验证过程 中以及采用相应分析方法时需要考虑

3、的因素。 本指导原则贯穿溶出度实验的全部 过程，并对方法提供了指导和验证标准。同时它还涉及对普通制剂和缓释制剂所 生成的数据和接受标准进行说明。Scope范围Chapter <1092> addresses the developmentandvalidationof dissolution procedures, with a focus on solid oral dosage forms.Ma ny of the con cepts prese nted, however, may be applicable to other dosageforms and routesof

4、 administration.Gen eral recomme ndatio ns are give n with the un dersta nding that modificationsof the apparatus and procedures as givenin USP general chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。所提出的许多概念也可能适用于其他剂型和给药途径。关于设备和方法的修改部分在 USP通则中给出了合理的说明。The organizationof <109

5、2> follows the sequenee of actionsofte n performed in the developme nt and validati on of a dissoluti ontest. The secti ons appear in the follow ingseque nee.精品文档在进行溶解度实验的开发和验证时，常遵循指导原则<1092>,具体内容如下：1. PRELIMINARY ASSESSMENT （FOR EARLY STAGES OFPRODUCTDEVELOPMENT/DISSOLUTIONMETHOD DEVELOPME

6、NT）1. 前期评估（对产品开发以及溶出度方法开发的前期研究评估）1.1 Performing Filter Compatibility1.1滤膜相容性研究1.2 Determi ning Solubility and Stability of DrugSubsta nee inVarious Media1.2原料药在不同溶出介质中溶解度测定和稳定性研究1.3 Choos ing a Medium and Volume1.3溶出介质和体积选择1.4 Choos ing an Apparatus1.4溶出设备选择（桨法和篮法以及其他方法）2. METHOD DEVELOPMENT2. 方法开发2

7、.1 Deaerati on2.1脱气2.2 Si nkers2.2沉降篮2.3 Agitatio n2.3转速2.4 Study Design2.4研究设计2.4.1 TimePoi nts2.4.1 取样时间点2.4.2 Observatio ns243 Sampli ng243 取样244 Clea ning244 清洗2.5 Data Ha ndli ng2.5数据处理2.6 Dissoluti on Procedure Assessme nt2.6溶出方法评估3. ANALYTICAL FINISH3. 完成分析3.1 Sample Process ing3.1样品处理3.2 Fil

8、ters3.2过滤3.3 Ce ntrifugati on3.3 离心3.4 An alytical Procedure3.4分析方法3.5 Spectrophotometric An alysis3.5光谱分析3.6 HPLC3.6HPLC 法4. AUTOMATION4. 自动化4.1 Medium Preparati on4.1介质的配制4.2 Sample In troduct ion and Timi ng4.3 Sampling and Filtration4.3取样和过滤4.4 Clea ning4.4清洗4.5 Operati ng Software and Computati

9、o n of Results4.5操作软件和计算的结果5. VALIDATION5. 验证5.1 Specificity/Placebo Interferenee5.1专属性/安慰剂（辅料）干扰5.2 Lin earity and Range5.2线性和范围5.3 Accuracy/Recovery5.3准确度/回收率5.4 Precisi on5.4精密度5.4.1 REPEATABILITY OF ANALYSIS5.4.1 重复性5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS中间精密度/耐用性5.4.3 REPRODUCIBILITY5.4.3 重现性5.

10、5 Robust ness5.5耐用性5.6 Stability of Sta ndard and Sample Soluti ons5.6样品溶液和标准溶液的稳定性5.7 Con siderati ons for Automati on6. ACCEPTANCE CRITERIA6. 可接受标准6.1 Immediate-Release Dosage Forms6.1速释剂型6.2 Delayed-Release Dosage Forms6.2延迟释放剂型6.3 Exte nded-Release Dosage Forms6.3延长释放剂型6.4 Multiple Dissolutio n

11、Tests6.4多个溶解度试验6.5 Interpretation of Dissolution Results6.5溶出结果说明6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS6.5.1 即时释放剂型6.5.2 DELAYED-RELEASE DOSAGE FORMS延迟释放剂型6.5.3 EXTENDED-RELEASE DOSAGE FORMS6.5.3 延长释放剂型PRODUCTvolume溶出介质、1. PRELIMINARYASSESSMENT (FOR EARLY STAGES OF DEVELOPMENT/DISSOLUTION METHODDEVELO

12、PMENT)1.前期评估(产品开发/溶出度方法开发的初期阶段)Beforemethod developme nt can beg in, it is importa nt to characterize the molecule sothat the filter, medium, of medium, and apparatus can be chose n properly in order to evaluate the performa nee of the dosage form.在开始溶出方法开发之前，我们对用以评价制剂溶出行为的滤膜、 溶出介质体积和溶出设备进行适当的筛选是非常重

13、要的。1.1 Performing Filter Compatibility1.1滤膜相容性研究精品文档Filtrati on is a key sample-preparati on step in achiev ing accurate test results. Thepurpose of filtration is to remove un dissolved drug and excipie nts from thewithdraw n soluti on. If not removed from the samplesolution,particles of thedrugwill

14、 continue to dissolve and can bias the results. Therefore, filteringthe dissolution samples is usually necessary and should be doneimmediatelyifthe filter is not positioned onthe cannu la.为获得准确试验结果，过滤是样品制备的一个关键步骤。过滤的目的是为了 除去溶出液中未溶解的药物和辅料。如果不把未溶解的药物和辅料从样品溶液中 除去，那么未溶解的药物颗粒将会继续溶解使试验结果出现偏差，因此，如果取样管中没有过滤

15、器，应立即对溶出度样品进行过滤。Filtrati onalso removesin solubleexcipie ntsthat may otherwiseinterferewith the analytical finish. Selectionof the proper filtermaterial is importa nt and should be accomplished, andexperimentallyjustified, early in thedevelopmentof thedissoluti on procedure. Importa nt characteristi

16、cs to con sider when choosinga filtermaterial are type, filter size, and poresize. The filter that is selectedbased on evaluation during the early stages of dissolution procedure developmentmayneedto be rec on sidered at a later time point. Requalificati on has to beconsideredafter a change in compo

17、sitionof the drugproduct or cha nges in thequality of the in gredie nts (e.g.particle size of microcrystalline cellulose).过滤也可除去可能会干扰分析测定的不溶性辅料。选择适当的过滤材料是非 常重要，应该在早期溶出方法开发的过程中通过实验确定和完成。在选择滤膜时有必要重点考虑滤膜的材料、型号和孔径大小。通常对早期阶段溶出方法开发过 程的评价选择过滤器，但在后期试验中如果制剂成分改变或组成成分质量变化可 能需要重新考虑过滤器，(例如：微晶纤维素粒径的改变)。Examples o

18、f filters used in dissolutiontestingcan be cannulafilters, filter disks or frits, filter tips, or syringefilters. The filter material has to be compatible with the media and the drug.Common pore sizes range from 0.20 to 70 mm, however, filters of other poresizes can be used as needed. If the drug su

19、bsta nee particle size is very small(e.g., microni zed ornan oparticles),it can be challe nging to find a filterpore sizethat excludes these small particles.用于溶出试验的过滤器有管路过滤器、过滤盘或玻璃过滤器、滤头或针头式 过滤器。过滤材料必须与介质和药物相适合。常见孔径大小范围：0.2070 ym，如果需要也可使用其他孔径大小的过滤器。如果原料药的粒度很小(例 如，微分化颗粒或纳米颗粒)，找到一个合适的过滤器过滤这些小颗粒至今仍具 有挑

20、战性。Adsorptionof the drug(s) by the filtermay occur and needsto be evaluated. Filter materials will in teract withdissoluti on media to affect the recovery of the in dividual solutes and mustbeconsideredon a case-by-casebasis.Differentfiltermaterialsexhibitdiffere ntdrug-b inding properties. Perce nt

21、ageof drug loss from the filtratedue to binding may be dependent on the drug concen trati on. Therefore theadsorptive in terfere nee should be evaluated on sample soluti ons at differentconcentrationsbracketing the expectedconcentrationrange.Where the drugadsorptionis saturable,discardinganinitial v

22、olume of filtrate may allow thecollection of a subseque nt solutio n that approaches the origi nal soluti onconcen trati on. Alter native filter materials that mini mize adsorptive in terfere nee can usually be found.Prewetti ng of the filter with the medium maybe n ecessary. In addition, it is impo

23、rtant that leachables from the filter donot interfere with the analytical procedure. This can be evaluated by an alyz in gthe filtered dissoluti on medium and comparing it with the unfiltered medium.过滤时可能会发生药物的吸附，需要进行评估。过滤材料将与溶出介质相互 作用，影响每个溶质的回收率应该根据具体问题进行考虑。不同的过滤材料表现出与药物结合的不同特性。由于药物与滤膜结合引起药物从滤液中损失的

24、比例， 可能依赖于药物浓度。因此，应采用预期浓度范围内不同浓度的样品溶液来评估 滤膜吸附干扰。由于药物吸附是可饱和的，弃去一定体积的初滤液，收集续滤液， 以达到接近原来的溶液浓度的样品也是可取的。通常选择适合的过滤材料，最大限度地减少滤膜吸附干扰，润湿滤膜对减少吸附也是必要的。此外，过滤后的溶出物不干扰分析检测也是非常重要的，这可以通过过滤后的溶出介质过滤与未过 滤的溶出介质进行比较，评估滤膜是否干扰分析测定。The filter size should be based on thevolume to be withdrawn and the amount of particles to b

25、e separated.Use of thecorrectfilter dime nsions will improve throughput andrecovery, andalso reduceclogging. Use of a large filter for small-volume filtration can lead to loss ofsample through hold-up volume, whereas filtrati on through small filter sizes needs higher pressures and Ion gertimes, and

26、 the filters can clog quickly.根据要过滤样品溶液的体积以及样品溶液中颗粒的量选择滤膜孔径。使用正确的滤膜孔径将提高溶液的通过率和回收率， 并减少滤膜堵塞。使用大孔径滤膜 过滤小体积溶液，能够导致样品溶液损失量过大而收集不到所用样品量；使用小 孔径滤膜过滤，需要更高的压力和较长的时间，并且溶液迅速堵塞滤膜。Filters used for USP Apparatus 4 n eedspecial atte nti onbecause they are in tegrated in the flow-through process.Undissolved partic

27、les may deposit on the filters, creati ng resista nee to theflow.USP仪器4中使用的过滤器需要特别注意，因为它们在流动过程中使用。不溶颗粒会沉积在过滤器，产生流动阻力of the filter withIn the case of automatedsystems,selectionregard to material and pore size can be done in asimilar manner to manualfiltration.Flow rate through the filter andcloggingm

28、aybe critical for filters used in automated systems.Experime ntalverificationthat a filter isappropriate may be accomplishedby comparingthe responsesfor filteredandunfilteredstandardand samplesolutions.This is done by firstpreparingasuitablestandardsolutionand a samplesolution.For example, prepare a

29、typical dissoluti on sample in a beaker and stir vigorouslywith a magneticstirrer to dissolve the drug load completely.For sta ndardsoluti ons,comparethe results for filteredsoluti ons(after discardi ng the appropriate volume) tothose for the unfiltered solutions. For sample solutions, compare the r

30、esultsfor filteredsoluti ons(after discardi ng the appropriatevolume) to those forcentrifuged, unfiltered solutions.在自动化系统的情况下，关于过滤器滤膜材料和孔径大小可以用类似的方式 通过手动过滤进行选择。在自动化系统中通过过滤器的流量和过滤器的堵塞可能 是至关重要的。通过试验比较过滤和未过滤的标准溶液和样品溶液的含量差别， 验证该过滤器是合适的。首先制备一个合适的标准溶液和样品溶液。例如，在烧 杯中制备一个标准溶解样品，用磁力搅拌器搅拌使药物完全溶解。对于标准溶液，比较过滤溶液

31、（弃去的适当体积后）和未过滤溶液的含量测定结果； 对于样品溶 液，比较过滤（弃去适当体积后）、离心、未过滤样品溶液的含量测定结果。1.2 Determi ningSolubility and Stability of DrugSubsta nee inVarious Media1.2原料药在不同溶出介质中的溶解度测定和稳定性研究Physical and chemical characteristics of the drug substanee need to be determ inedas part of the process of selectingthe proper dissolu

32、tion medium.Whendecidingthe compositionof the medium for dissolution testing, it is importantto evaluate the in flue nee of buffers, pH, and if n eeded,differe ntsurfactantsonthe solubility and stability of the drug substanee.Solubility of the drugsubsta nee is usually evaluated by determ ining the

33、saturatio n concen tratio n ofthe drug indiffere nt media at 37° using the shake-flask solubilitymethod(equilibriumsolubility). To level out potentialion effectsbetween thedrugand the buffers usedin themedia, mixturesof hydrochloric acidand sodiumhydroxide areusedto performsolubilityinvestigati

34、ons;this is in additiontothe typical bufferto evaluatetheo (i.e., be checked to solubility test.solutions.In certaincases, it may be necessarysolubility of the drug at temperatures other than 37 250). The pHof the clearsupernatant shoulddeterm ine whether the pH cha ngesduri ngtheAlter native approa

35、ches for solubility determ in ati onmay also be used.在选择合适溶出介质的过程中，需要确定原料药的物理化学特性。当需要确定溶出度试验中溶出介质的组成时，有必要评估缓冲液、pH值、以及不同的表面活性剂（如果需要）对药物的溶解度和稳定性的影响。在37 C温度条件下，采用摇瓶溶解法（平衡溶解度）测定原料药在不同介质中的饱和浓度，来评估药 物的溶解性。为了消除溶出介质中药物和缓冲液之间离子的潜在影响，使用盐酸和氢氧化钠的混合物对溶解度进行研究， 这是一种典型的缓冲溶液。在某些情况 下，评估药物在37 C以外条件下（即，25 C）的溶解度可能也是必要的

36、。在溶解度试验过程中应检查上清溶液的 pH值，以确定在溶解过程中pH值是否 改变。也可使用其他可供选择的方法进行溶解度测定。Typical media for dissoluti on mayin elude the followi ng (notlisted in order of preferenee):diluted hydrochloricacid, buffers(phosphate or acetate) in the physiologic pH range of 1.2 - 7.5, simulatedgastric or in test inal fluid (with or

37、 without en zymes),a nd water. For somedrugs, in compatibility of the drug with certa in buffers or salts may in flue ncethe choice of buffer. The molarity of the buffers and acids used can in flue ncethe solubiliz ing effect, and this factor may be evaluated.溶出的典型介质包括(未按照优先顺序列出)：稀盐酸、在生理pH值范围为1.2-7.

38、5缓冲溶液(磷酸盐或者醋酸盐)、模拟胃液或肠液(含有或不含有酶)和水。对于一些药物，与药物不相容的特定缓冲液或盐可能会影响缓冲剂的 选择。所使用的缓冲液和酸的体积摩尔浓度能够改变药物的增溶作用，这个因素也需要评估。Aqueoussolutions(acidic or buffersolutions) may contain aperce ntage of a surfacta nt e.g., sodium dodecylsulfate(SDS),polysorbate, or lauryldimethylamineoxide to enhancethesolubility of the dr

39、ug. The surfacta nts selected for the solubility inv estigati ons should cover all com mon surfacta nt types, i.e., anionic,nonionic, and cati onic. When a suitable surfactanthas been identified,differentconcentrationsof thatsurfacta nt should be inv estigated to ide ntifythe lowest concen trati on

40、n eededto achieve sink con diti ons. Typically,the surfacta ntconcentrationis above its critical micellarconcentration(CMC).Table 1 shows a list of some of the surfacta nts usedin dissoluti on media. Approximate CMC values are provided with refere nceswhe navailable. The list is not comprehe nsive a

41、nd is not intendedto exclude surfactantsthat are not listed.Other substances, such ashydroxypropyl b -cyclodextrin,have bee n used as dissoluti on media additives to enhance dissoluti on of poorlysoluble compo un ds.The U.S. Food andDrug Administration(FDA) maintainsadatabase of dissolutionmethods,i

42、ncludinginformation on dissolution mediathat havebeen used(1) . Typically, the amount of surfactant addedissufficientto achieve sink conditionsin the desired volumeof dissoluti onm edium.有时候水溶性介质中（酸性水溶液或缓冲溶液）可能添加一定比例的表面活 性剂（如十二烷基硫酸钠（SDS ），聚山梨醇酯，或十二烷基二甲基氧化胺） 以提高药物的溶解度。选择用于溶解度研究的表面活性剂时应涵盖所有常用种类 的表面活性剂

43、，比如阴离子、非离子型和阳离子，当已经确定一个合适的表面活 性剂时，应对表面活性剂的不同浓度进行研究，以确定达到漏槽条件所需的最低浓度。一般情况下，表面活性剂的浓度高于它的临界胶束浓度（CMC ）。表1列出了溶出介质中常用的表面活性剂，表中提供了CMC的近似临界值，以便我们参考，此外，表中所列表面活性剂并不全面，不能排除未列出的表面活性剂。 其他表面活性剂，如羟丙基B -环糊精，已被用来作为溶出介质添加剂提高难溶性化合物的溶解度，美国食品药品管理局（FDA ）溶出度数据库中，已经收载 含有羟丙基B -环糊精的溶出介质（1 ）。通常情况下，表面活性剂的加入量以 满足达到漏槽条件所需的溶出介质体积

44、。It is important to controlthegrade and purity of surfactantsbecause use of differentgrades could affectthe solubility ofthe drug. For example, SDS is available in both a technicalgrade and a high-purity grade. Obtaining polysorbate 80 from differe nt sourcesca n affect its suitability whe n perform

45、 ing high-performa nee liquidchromatography （HPLC） an alysis.由于使用不同级别的表面活性剂会影响药物的溶解度，因此要控制表面活性 剂的级别和纯度。例如，SDS只有在工业级和高纯度级才可以使用。在使用 HPLC方法进行分析时，不同来源的聚山梨酯（吐温） 80会影响它的适用性。 There may be effects of counter-ions orpH on the solubility or solution stability of the surfactantsolutions.Forexample,a precipitat

46、e forms when the potassium salt for the phosphate bufferis used at a concen trati on of 0.5 M in comb in ati on with SDS. This can beavoided by using the sodium phosphate salt when preparing media with SDS.反离子或pH值可能会影响表面活性剂溶液的溶解性或稳定性。例如，当含有SDS的磷酸盐缓冲液中钾盐浓度为 0.5mol/L时，就形成了沉淀析出，但是使用磷酸钠制备含有SDS的介质时，可以避免这

47、种现象发生。Table 1. CommonlyUsed Surfactantswith Critical MicelleConcen trati ons表1常见表面活性剂的临界胶束浓度CMC (%釜董桂科-二堤遷云驳骑(SDS.SLS)心0.18%-0.23%2斗0.2嫁01曲0.12%-六烷基三甲基溟化铁(CIAB)羊0.033°c-0 036%(092-LOmW Q节索螯冬(季齧超迈X应0一 1即曲4也1)心CLO 了 強-0 09% 心菱襄酹加£吐型80)护0.02%-0.0843.7去薮.矣敦鹫己二醇m沖葩 Labrasol ?0.01*4扣梵走二吟乏氏扫35 &l

48、t;Cretnophor EL? “裴喘工坪弓咗露花:Bnj35)卢幸三發薛CTriton X-100)户W密基二卓墓誉W复化勵(LDAO) P0.023UpRout in ely, the dissoluti on mediumis buffered; however, theuseof purified water as the dissolution medium is suitable for products with adissoluti on behavior in depe ndent of thepH of the medium. There are severalreaso

49、nswhy purified watermay not be preferred.The water qualitycan varydependingon its source, and the pH of the water is not as strictlycon trolledasthe pH of buffersoluti ons.Additi on ally,the pHcan vary from day to daya nd can also cha nge duri ng therun, dependingon the drugsubstaneeandexcipients. U

50、se ofan aqueous - orga nic solve nt mixture as a dissoluti onmediumis discouraged; however,with proper justificatio n this type of medium may beacceptable.通常，溶出介质为缓冲盐溶液，但是，对于非pH值依赖性的制剂可以使用 纯化水作为溶出介质。不推荐使用纯化水作为溶出介质的原因： 水的质量变化取 决于它的来源，而水的pH值不像缓冲溶液能够严格控制；此外，若药物和辅料 的溶出对pH值敏感时需要考虑使用缓冲液。另外使用水-有机溶剂混合物作为 溶出

51、介质也是不推荐的，但是，特殊情况下（有充分适当的理由），也是可以接 受的。Inv estigatio ns of the stability of thedrug substa nee shouldbe carried out, whe n n eeded, in the selecteddissolutio nm edium with excipie nts prese nt, at 37°. Thiselevated temperature has thepote ntial to decrease solutio nstability（degradatio n）.Stabili

52、ty should allowfor sufficie nt timeto complete or repeat the an alytical procedure.Physicalstability may be of concern when precipitationoccursbecause of lowersolubility at room or refrigerated temperature.必要时，应该对原料药的稳定性进行考察，在所选择的溶出介质中加入辅料， 在37 C条件下进行考察。这种升高的温度会潜在的降低溶液的稳定性（降解）稳定性试验应考虑到有足够的时间来完成或重复分析

53、过程。当因室温或冷藏贮存时降低药物的溶解度而发生沉淀时，物理稳定性也需要关注。1.3 Choos ing aMedium and Volume1.3溶出介质和体积的选择When developinga dissolution procedure, one goal is to havesinkconditions, which are defined as having a volume ofmedium at least three timesthe volume required to form a saturated soluti on of drug substa nee. When

54、sinkcon diti ons are present, it is more likely that dissolution results will reflectthe properties of the dosage form. A medium that fails to provide sinkconditions may be acceptable if it is appropriately justified. The compositionand volume of dissoluti on medium are guided by the solubility in v

55、estigati on s.Forexample, the choice and concen trati onofa surfactant need to be justifiedfrom the solubility data and the dissolution profiles.当开发一个溶出试验方法时，首先要满足漏槽条件，漏槽条件定义为溶出介 质体积至少为药物达到饱和溶液所需体积的三倍。当满足漏槽条件后，溶出度结 果能够更好的反映药物制剂的质量。在适当条件下，介质不满足漏槽条件也是可以接受的。溶解介质的组成和体积应根据溶解度的试验结果进行调整。例如，表面活性剂种类和浓度选择，需要根

56、据药物溶解度数据和溶出曲线进行调整。The use ofenzymesin the dissolutionmediumis permitted,in accorda nee withDissoluti on<711>, whe n dissoluti ongelat incapsulesfailures occur as a result of cross-linkingwithor gelatin-coatedproducts. A discussionof thephenomenonof crosslinking and method development using enz

57、ymes can be found in Capsules Dissoluti onTesti ng and Related QualityAttributes <1094>. Validati on should be performed with themethod using en zymesaccord ing to sect ion5. Validati on当交联明胶胶囊或明胶包衣的制剂溶出失败时，在溶出介质中允许加入酶， 这同溶出度 <711> 指导原则一致。在 “ Capsules - Dissolutio n Testi ng中可以找到发生交联现象的and RelatedQuality Attributes<1094>讨论和采用酶进行方法开发的研究。根据 第5节验证，使用酶方法按照溶出度 方法学验证的要求进行验证。Ano ther opti on is to use media tha